This study examined the relationship between religiosity, spirituality and mental health in the context of a stress-coping framework. Participants were 135 rural, low-income HIV-positive adults in Iringa, Tanzania. The relationships between religiosity, spirituality, coping responses, social support, and psychological distress (depression, anxiety, and stress) were examined using structural equation modeling. Religiosity was related to decreased avoidant coping and increased social support, which in turn were related to psychological distress. Spirituality was positively related to active coping and social support. Results suggest that coping strategies and social support may mediate the relationship between religiosity and spirituality and psychological distress. Interventions to reduce psychological distress among HIV-positive individuals in Tanzania might incorporate strategies to reduce avoidant coping and increase social support. According to the present findings, this may be accomplished through faith-based approaches that incorporate religious and spiritual activities into HIV prevention programs.